CN112724175A - Minodronic acid calcium complex and preparation method thereof - Google Patents
Minodronic acid calcium complex and preparation method thereof Download PDFInfo
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- CN112724175A CN112724175A CN202011608714.2A CN202011608714A CN112724175A CN 112724175 A CN112724175 A CN 112724175A CN 202011608714 A CN202011608714 A CN 202011608714A CN 112724175 A CN112724175 A CN 112724175A
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- calcium
- minodronate
- minodronic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a minodronate calcium complex and a preparation method thereof, wherein the chemical formula is Ca (Min)2(2H2O), wherein Ca represents calcium, Min represents minodronic acid, H2O represents water, the crystal system is monoclinic system, the space group is C2/C, and the lattice constant is
β 106.444 ° and z 4. The method comprises the steps of taking calcium salt and minodronic acid as raw materials, taking deionized water as a solvent, adjusting the pH value to 3-5 by using a sodium hydroxide solution, standing for 3-24 hours at 20-200 ℃, filtering, washing and drying to obtain a colorless transparent parallelogram crystal, namely the minodronic acid calcium complex. The preparation method of the invention is extremely simple, the crystal growth speed is moderate, the stress is small, the uniformity is good, the crystal has very complete appearance, and the invention can be used for medicine slow release, targeted delivery, bone tissue repair and the likeThe field has important potential application prospect.
Description
Technical Field
The invention relates to the technical field of biomedical materials, in particular to a minodronate calcium complex and a preparation method thereof.
Background
Coordination polymers are a class of compounds formed by the bonding of metal ions and organic ligands through coordination bonds. In recent years, the development of coordination polymer chemistry has led to new research and application in the fields of design, synthesis, structure, performance, etc., and has become a leading and hot topic in the disciplines of organic, inorganic, materials, biology, medicine, etc. The complex with a novel structure is designed and constructed by utilizing the molecular self-assembly principle, so that the complex has a specific biological function and has important practical significance for wide application in the biomedical field.
Minodronic acid is a bisphosphonic acid micromolecule drug which is widely applied to clinical treatment for resisting osteoporosis, osteitis deformans and bone-related tumors. However, the existing bisphosphonic acid (or sodium salt) has stronger water solubility, and the concentration threshold for effective action is very low, and adverse reaction is easily caused when the threshold is exceeded, so that direct injection or load slow release by using a delivery system can be generally carried out, and the application of molecules with remarkable osteogenesis effects, such as bisphosphonates, in bone regeneration and repair is limited to a certain extent. Thus, the search for other bisphosphonates having a significantly lower solubility or degradation rate than bisphosphonic acids (or sodium salts) is of great importance for their further application in the field of bone repair.
The diphosphonic acid structure contains two phosphonate groups, most of ionized ionic forms in water are bidentate or polydentate ligands, and the diphosphonic acid structure is extremely easy to chelate multi-coordinated metal ions such as calcium ions and the like to form a metal organic complex which has stable physical and chemical properties and is difficult to dissolve, so that the slow release of the diphosphonic acid molecules in an aqueous solution is realized. Therefore, the complex has potential application value in the fields of material science, biomedicine and the like. Therefore, the minodronic acid is used as a ligand to react with calcium ions to prepare the minodronic acid calcium complex, the preparation method is extremely simple, the crystal growth speed is moderate, the stress is small, the uniformity is good, the crystal has very complete appearance, the crystal is not easy to dissolve in water, and the minodronic acid calcium complex has important potential application prospects in the fields of drug slow release, targeted delivery, bone tissue repair and the like.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides a minodronate calcium complex and a preparation method thereof.
In order to achieve the purpose, the technical scheme provided by the invention is as follows: a calcium minodronate complex with chemical formula of Ca (Min)2(2H2O), wherein Ca represents calcium, Min represents minodronic acid, H2O represents water, the crystal system is monoclinic system, the space group is C2/C, and the lattice constant is
β＝106.444°，z＝4。
Further, the shape of the compound is colorless transparent parallelogram in aqueous solution, and the parallelogram becomes smaller with the increase of pH.
The invention also provides a preparation method of the minodronate calcium complex, which comprises the steps of taking calcium salt and minodronate as raw materials, taking deionized water as a solvent, adjusting the pH value to 3-5 by using a sodium hydroxide solution, standing for 3-24 hours at 20-200 ℃, filtering, washing and drying to obtain a colorless transparent parallelogram crystal, namely the minodronate calcium complex; wherein the reaction time and the reaction temperature are inversely related, i.e., the higher the temperature, the shorter the reaction time.
Further, the concentration of the minodronic acid is 3-15 mmol/L.
Further, the molar ratio of the calcium salt to the minodronic acid is 1: 2-2: 1.
Further, the calcium salt is any one of calcium chloride, calcium nitrate, calcium hydroxide and calcium phosphate.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the calcium minodronate complex is prepared by taking calcium salt and minodronic acid as raw materials and adopting a standing method, and has the advantages of extremely simple preparation method, moderate crystal growth speed, small stress, good uniformity and very complete appearance. The complex takes calcium as a central atom and minodronic acid as a ligand, and presents a spatial zero-dimensional island structure. The minodronate calcium complex has important potential application prospects in the fields of drug slow release, targeted delivery, bone tissue repair and the like, and is worthy of popularization.
Drawings
FIG. 1 is a crystal diagram of a calcium minodronate complex.
FIG. 2 is a structural unit diagram of a minodronate calcium complex.
FIG. 3 is a thermogravimetric plot of a calcium minodronate complex.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the present invention is not limited thereto.
Example 1
Weighing 98% minodronic acid (0.0096g, 0.03mmol) and 98% calcium chloride (0.0033g, 0.03mmol), adding into 10mL of water, slowly dropping 0.1mol/L NaOH solution, stirring to make the solution clear and transparent, adjusting pH to 3, transferring the solution into a penicillin bottle, covering, screwing, placing the penicillin bottle into a thermostat, reacting at 20 ℃ for 24 hours, filtering, washing, and drying to obtain a larger colorless transparent parallelogram crystal with a regular shape, namely the minodronate calcium complex. Wherein the reaction time and the reaction temperature in the preparation process are in negative correlation, namely the higher the temperature is, the shorter the reaction time is; the prepared minodronate calcium complex is a colorless transparent parallelogram crystal in the shape of an aqueous solution, and the rectangle becomes smaller and smaller with the increase of pH.
FIG. 1 is a scanning electron microscope photograph of a crystal of a calcium minodronate complex, from which it can be seen that the calcium minodronate complex is a parallelogram crystal.
To minodronate calcium crystalPerforming single crystal test and analysis to obtain a structural unit diagram of the complex, as shown in FIG. 2, wherein the chemical formula of the minodronate calcium complex is Ca (Min)2(2H2O), wherein Ca represents calcium, Min represents minodronic acid, H2O represents water, the crystal system is monoclinic system, the space group is C2/C, and the lattice constant is
β 106.444 ° and z 4. The central metal calcium atom is hexa-coordinated with 4O (from two minodronate ligands, respectively) and 2O (from a water ligand), respectively, to form an octahedral structure.
Thermodynamic analysis is carried out on the minodronate calcium crystal to obtain a thermogravimetric curve of the complex, as shown in figure 3, the temperature of the coordination removal water of the minodronate calcium complex is above 100 ℃, and the decomposition temperature exceeds 200 ℃, which shows that the complex has good thermal stability.
Example 2
Weighing 98% minodronic acid (0.0161g, 0.05mmol) and 98% calcium hydroxide (0.0074g, 0.1mmol), adding into 10mL of water, slowly dropping 0.1mol/L NaOH solution, stirring to make the solution clear and transparent, adjusting pH to 4, transferring the solution into a penicillin bottle, covering, screwing, placing the penicillin bottle into a thermostat, reacting at 80 ℃ for 18 hours, filtering, washing, and drying to obtain a larger colorless transparent parallelogram crystal with a regular shape, namely the minodronate calcium complex.
Example 3
Weighing 98% minodronic acid (0.0322g, 0.1mmol) and 98% calcium nitrate (0.0082g, 0.05mmol), adding into 10mL of water, slowly dropping 0.1mol/L NaOH solution, stirring to make the solution clear and transparent, adjusting pH to 5, transferring the solution into a 15mL reaction kettle, covering, screwing, placing the reaction kettle in a thermostat, reacting at 150 ℃ for 12 hours, filtering, washing, and drying to obtain a moderate colorless transparent parallelogram crystal with a regular shape, namely the minodronate calcium complex.
Example 4
Weighing 98% minodronic acid (0.0483g, 0.15mmol) and 98% calcium chloride (0.0166g, 0.15mmol), adding into 10mL of water, slowly dropping 0.1mol/L of NaOH solution, stirring to make the solution clear and transparent, adjusting pH to 5, transferring the solution into a 15mL reaction kettle, covering, screwing, placing the reaction kettle in a thermostat, reacting at 200 ℃ for 6 hours, filtering, washing, and drying to obtain a moderate colorless transparent parallelogram crystal with a regular shape, namely the calcium minodronate complex.
Example 5
Weighing minodronic acid (0.0096g, 0.03mmol) with the purity of 98 percent and calcium phosphate (0.0465g, 0.15mmol) with the purity of 98 percent, adding the minodronic acid and the calcium phosphate into 10mL of water, slowly dripping 0.1mol/L NaOH solution, stirring to ensure that the solution is clear and transparent, adjusting the pH value to 3, transferring the solution into a 15mL reaction kettle, covering, screwing, placing the reaction kettle into a constant temperature cabinet, reacting for 3 hours at 200 ℃, filtering, washing and drying to obtain a small flat rectangular transparent crystal with a regular shape, namely the minodronic acid calcium complex.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (6)
1. A minodronate calcium complex is characterized in that the chemical formula is Ca (Min)2(2H2O), wherein Ca represents calcium, Min represents minodronic acid, H2O represents water, the crystal system is monoclinic system, the space group is C2/C, and the lattice constant is
β＝106.444°，z＝4。
2. The calcium minodronate complex according to claim 1, wherein: the appearance of the nano-structure is colorless transparent parallelogram in pure water solution, and the parallelogram is smaller and smaller along with the increase of pH.
3. A method for preparing the calcium minodronate complex according to claim 1, which comprises the steps of: the method comprises the steps of taking calcium salt and minodronic acid as raw materials, taking deionized water as a solvent, adjusting the pH value to 3-5 by using a sodium hydroxide solution, standing for 3-24 hours at 20-200 ℃, filtering, washing and drying to obtain a colorless transparent parallelogram crystal, namely a minodronic acid calcium complex; wherein the reaction time and the reaction temperature are inversely related, i.e., the higher the temperature, the shorter the reaction time.
4. The method for preparing a calcium minodronate complex according to claim 3, wherein: the concentration of the minodronic acid is 3-15 mmol/L.
5. The method for preparing a calcium minodronate complex according to claim 3, wherein: the molar ratio of the calcium salt to the minodronic acid is 1: 2-2: 1.
6. The method for producing a calcium minodronate complex according to claim 3 or 5, wherein: the calcium salt is any one of calcium chloride, calcium nitrate, calcium hydroxide and calcium phosphate.
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| CN202011608714.2A CN112724175A (en) | 2020-12-30 | 2020-12-30 | Minodronic acid calcium complex and preparation method thereof |
| PCT/CN2021/121012 WO2022142539A1 (en) | 2020-12-30 | 2021-09-27 | Minodronate calcium complex and preparation method therefor |
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| WO2022142539A1 (en) * | 2020-12-30 | 2022-07-07 | 华南理工大学 | Minodronate calcium complex and preparation method therefor |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070088161A1 (en) * | 2005-10-19 | 2007-04-19 | Stockel Richard F | Novel chelated bisphosphonates for use as pharmaceutical agents |
| WO2012042024A1 (en) * | 2010-10-01 | 2012-04-05 | Istituti Fisioterapici Ospitalieri | Self-assembling nanoparticles for the release of bisphosphonates in the treatment of human cancers |
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| EP1267890A2 (en) * | 2000-04-07 | 2003-01-02 | The Board of Regents of The University of Texas System | Unique compositions of zwitterionic phospholipids and bisphosphonates and use of the compositions as bisphosphate delivery systems with reduced gi toxicity |
| CN101530415A (en) * | 2008-03-10 | 2009-09-16 | 北京德众万全医药科技有限公司 | Pharmaceutical composition containing bisphosphates and preparation method thereof |
| EP3180036B1 (en) * | 2015-04-24 | 2018-11-28 | Duke University | Metal complexes with bisphosphonate useful as imaging agents |
| CN106006593B (en) * | 2016-05-18 | 2018-08-17 | 西南交通大学 | A kind of nano-calcium phosphate preparation method of simple and effective |
| CN111068109A (en) * | 2019-12-20 | 2020-04-28 | 华南理工大学 | Method for constructing calcium biphosphate crystals on surface of composite support and product |
| CN112724175A (en) * | 2020-12-30 | 2021-04-30 | 华南理工大学 | Minodronic acid calcium complex and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070088161A1 (en) * | 2005-10-19 | 2007-04-19 | Stockel Richard F | Novel chelated bisphosphonates for use as pharmaceutical agents |
| WO2012042024A1 (en) * | 2010-10-01 | 2012-04-05 | Istituti Fisioterapici Ospitalieri | Self-assembling nanoparticles for the release of bisphosphonates in the treatment of human cancers |
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| EDITORS Z. AMJAD: "《Mineral Scale Formation and Inhibition》", 31 December 1995 * |
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| WO2022142539A1 (en) * | 2020-12-30 | 2022-07-07 | 华南理工大学 | Minodronate calcium complex and preparation method therefor |
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